Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. To date, there is still no effective antihypercholesterolemic agent commercially available that has found wide patient acceptance. The bile acid sequestrants seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
There are agents known, however, that are very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. These agents include the natural fermentation products compactin and mevinolin and a variety of semi-synthetic and totally synthetic analogs thereof.
The naturally occuring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR1## wherein:
R.sup.3 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting phenyl, dimethylamino, or acetylamino; and
R.sup.4 is: ##STR2## wherein Q is ##STR3## R.sup.5 is H or OH; M is ##STR4## R.sup.6 is hydrogen or hydroxy;
R.sup.7 is hydrogen or methyl; and a, b, c, and d represent single bonds, one of a, b, c or d represents a double bond, or both a and c or both b and d represent double bonds provided that when a is a double bond, Q is ##STR5## and when d is a double bond, M is ##STR6##
U.S. Pat. No. 4,517,373 discloses semi-synthetic hydroxy containing compounds represented by the above general formula wherein R.sup.4 is ##STR7##
U.S. Pat. Nos. 4,537,859 and 4,448,979 also disclose semi-synthetic hydroxy-containing compounds represented by the above general formula wherein R.sup.4 is ##STR8##
These compounds are prepared by the action of certain microorganisms on the corresponding non-hydroxylated sybstrates. One such organism described in U.S. Pat. No. 4,537,859 is of the genus Nocardia.
U.S. Pat. No. 4,376,863 discloses a fermentation product, isolated after cultivation of a microorganism belonging to the genus Aspergillus, which has a hydroxy containing butyryloxy side chain and is represented by the above general formula wherein R.sup.4 is ##STR9##
Japanese unexamined patent application No. J59-122, 483-A discloses a semi-synthetic hydroxy-containing compound respresented by the above general formula wherein R.sup.4 is ##STR10##
U.S. patent application Ser No. 877,041 filed June 23, 1986 discloses 6-substituted compounds of the above gneral formula wherein R.sup.4 is ##STR11## wherein n' is 1 to 5
R.sup.1 is hydrogen or C.sub.1-5 alkyl PA1 R.sup.2 is CH.sub.2 OH or CO.sub.2 R
The compounds of U. S. patent application Ser. No. 877,041 were prepared by a microbiological conversion of mevinolin or an analog thereof with a 6-methyl substituent.
The literature discloses a reaction known as the Barton Reaction by which a hydrogen in the .delta. position to an OH group can be abstracted to afford a carbon radical which can be oxidized. (See Hesse Adv. Free-Radical Chem. 3, 83-137 (1969); Barton, Pure Appl. Chem. 16, 1-15 (1968); Arthar, Adv. Photochem. 2, 263-304 (1964).